Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease

Recently, TDP-43, a 43 kDa nuclear TAR DNA-binding protein, was identified as the major disease protein in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), FTLD-U with motor neuron disease (FTLD–MND), and amyotrophic lateral sclerosis. To date, TDP-43 pathology in sporadic FTLD–MND has been reported only in select central nervous system areas. However, this distribution of lesions is insufficient to explain all clinical signs of FTLD–MND and the extent of TDP-43 pathology, throughout the brain, remains unknown. Therefore, as a pilot study, we performed an immunohistochemical whole brain scan of two cases diagnosed clinically as FTLD–MND and two control subjects. We found evidence of both neuronal and glial TDP-43 pathology in multiple brain areas including the nigro-striatal system, neo- and allocortical brain areas, with varying frequency, morphology, and degree, and nowhere in control tissue. The finding of a distinct cytopathological profile consisting of a cell nucleus devoid of endogenous TDP-43 staining coupled with diffuse/granular cytoplasmic staining (“pre-inclusion”) was prominent in a couple of brain areas. These pre-inclusions were not or only weakly ubiquitin-immunoreactive. While the findings of severe involvement of extracortical or extrapyramidal areas are strongly suggestive for FTLD–MND being a TDP-43 multisystem proteinopathy rather than a disease predominantly affecting the cortex and spinal cord, more detailed clinicopathological studies of larger cohorts are needed to fully elucidate the distribution and severity of pathological TDP-43 in this disease.